Method for making and measuring a coating on the surface of a medical device using an ultraviolet laser

ABSTRACT

This invention relates to a method for manufacturing an implantable medical device, having a surface covered with a coating that can include a desired amount of a biologically active material, using an ultraviolet (UV) laser. The invention also pertains to a method for manufacturing an implantable medical device having a surface covered with a coating having more than one layer wherein a desired portion of the top layer is ablated with an ultraviolet (UV) laser. Also, the invention relates to a method for measuring a thickness of a coating applied to an implantable medical device. Furthermore, the invention is directed to a method for manufacturing an implantable medical device having a surface covered with a coating free of webbing or cracking.

FIELD OF THE INVENTION

[0001] This invention relates generally to a method for manufacturing animplantable medical device. More specifically, the invention relates toa method for manufacturing an implantable medical device having a coatedsurface. More particularly, the invention is directed to a method formanufacturing an implantable medical device, having a surface coveredwith a coating that can include a desired amount of a biologicallyactive material, using an ultraviolet (UV) laser. The invention alsopertains to a method for manufacturing an implantable medical devicehaving a surface covered with a coating having more than one layerwherein a desired portion of the top or outer layer is ablated with anultraviolet (UV) laser. Also, the invention relates to a method formeasuring a thickness of a coating applied to an implantable medicaldevice. Furthermore, the invention is directed to a method formanufacturing an implantable medical device having a surface coveredwith a coating free of webbing or cracking.

BACKGROUND OF THE INVENTION

[0002] There are various kinds of medical devices that can be implantedin a human body. For example, medical devices, such as stents, areimplanted into a body lumen, such as a blood vessel, where it stayspermanently, to keep the vessel open and to improve blood flow to theheart muscle and relieve symptoms and used to reduce restenosis afterballoon angioplasty or other procedures involving catheters. Usually,the suitable stents include a stent having a cylindrical shape. Thewalls of the cylindrical structure can be formed of metal or polymerwith openings therein, e.g., a mesh. The medical devices can also bepositioned in other parts of the body, such as the kidneys or the brain.The procedure for implanting the medical device is fairly common, andvarious types of medical devices or stents have been developed andactually used.

[0003] To make the medical device surface more biocompatible, they havebeen coated with polymers. Further, there are various types of polymercoatings for medical devices that may contain a biologically activematerial, such as a drug, that are delivered to an afflicted area of abody. Drugs may be either bonded chemically, physically or absorbed inthe polymer matrix of the coating. Also, for the purpose of obtainingdrug delivery medical devices or stents, the drugs may be directlycoated or immobilized onto the devices, e.g. using a binding moleculebetween the drug molecule and the device surface. For example, U.S. Pat.No. 6,099,562 to Ding et al. discloses a stent having an undercoatcontaining a biologically active material covered by a topcoatsubstantially free of pores, and U.S. Pat. No. 5,879,697 to Ding et al.discloses a coated stent wherein the coating contains a reservoir layercontaining a biologically active material. Pinchuk, in U.S. Pat. No.5,092,877, discloses a stent of a polymeric material that may have acoating associated with the delivery of drugs. A patent to Sahatjian,U.S. Pat. No. 5,304,121, discloses a coating applied to a stentconsisting of a hydrogel polymer and a pre-selected drug such as cellgrowth inhibitors or heparin. Thus, a number of various coatings formedical devices have been used. Such coatings have been applied to thesurface of a medical device mostly by either spray-coating ordip-coating the device with a coating solution.

[0004] When a drug whose dosage must be strictly controlled is containedin the coating of the medical device, the amount of coating present onthe medical device must be accurately adjusted. Previously, the only wayto adjust the amount of coating on a medical device is to control theprocess parameters used to spray-coat the coating composition on thesurface of the medical device to form the coating, such as controllingthe spraying time and the flow rate of the coating solution. However,such control does not permit sufficiently accurate placement of thedesired amount of coating material or drug contained in the coatingmaterial to be placed on the medical device. Also, when a dip coatingmethod is used to form the coating, the amount of coating placed on thesurface of the medical device cannot be controlled precisely. Inaddition, no matter what method is used for forming the coating, therehas been no way to efficiently remove or trim excess or undesiredcoating from the coated medical device. Therefore, a method tomanufacture a medical device having a desired amount of coating isneeded.

[0005] Also, due to complex geometry of certain medical devices such asa stent, a webbing of coating material can form in the openings of thesemedical devices. More specifically, for instance, when a stent havingopenings in its sidewall is coated with a coating material, webbings,bindings or bridges of the coating material can form in the openings, atsmall gaps or corners between stent struts. This is especially true,when the stent has struts that are very close to each other or hasstruts that have bends in them. However, there has been no efficient wayto remove or trim such webbings, bindings or bridges of coatingmaterial. Hence, an object of the invention is to provide a method toremove or trim this webbing, binding or bridging from a coated medicaldevice.

[0006] In addition, it is not always desirable to have an even oruniform coating on an entire coated surface of a medical device. Forexample, depending on its geometry, a stent may have a portion where athick coating may easily crack and cause problems. More specifically,when a self-expandable stent is placed into its restrained state, itsstruts lie in close proximity to each other. The coating on some strutsmay adhere to coating on other struts. When the stent is expanded, theadhered coating may be torn off. Likewise when a balloon-expandablestent is collapsed for implantation, the coating on certain struts mayadhere to the coating on other struts because the struts are placed inclose proximity to each other. Such adhered coating may be cracked orremoved from the struts when the stent is expanded. If a portion of thecoating can be removed from the struts so that the coating on the strutsare made thinner and less likely to adhere to each other, the crackingof the coating may be reduced. However, previously, there has been noway to efficiently make a portion of a coating on a stent thinner. Thus,a further object of the invention is to provide a method to thin aportion of the coating on a medical device.

SUMMARY OF THE INVENTION

[0007] These and other objectives are accomplished by the presentinvention. To achieve the aforementioned objectives, a method has beeninvented for manufacturing an implantable medical device having asurface adapted for exposure to body tissue of a patient, wherein atleast a portion of the surface is covered with a coating having adesired amount of a biologically active material. Specifically, in themethod, a coating composition containing the biologically activematerial is applied to a portion of the surface of the medical device ina manner such that a coating containing an amount of the biologicallyactive material in excess of the desired amount of biologically activematerial is formed. Then the amount of biologically active material inthe coating that is in excess of the desired amount of biologicallyactive material is determined. A portion of the coating is ablated usingan ultraviolet (UV) laser in order to remove the coating containing theexcess biologically active material.

[0008] Another embodiment of the present invention is a method formanufacturing an implantable medical device having a surface adapted forexposure to body tissue of a patient, wherein at least a portion of thesurface is covered with a coating having at least two layers andcontaining a biologically active material. In the method, a firstcoating composition and a second composition are applied, in turn, on atleast a portion of the surface of the medical device. A portion of thesecond coating layer is then ablated using an ultraviolet (UV) laser.

[0009] Yet another embodiment of the invention is a method for measuringa thickness of a coating applied to at least a portion of a surface ofan implantable medical device. In the method, a portion of the coatingis ablated with an ultraviolet (UV) laser having pulse length shorterthan about 100 nanoseconds and a repetition rate less than about 100Hertz to expose a portion of the surface of the medical device and tocreate a step having a height in the coating. The thickness of thecoating is determined by measuring the height of the step by using awhite light interferometer.

[0010] Furthermore, another embodiment of the present invention is amedical device having a surface adapted for exposure to body tissue of apatient, wherein the surface has a plurality of openings therein andwherein at least a portion of the surface is covered with a coating in amanner such that the openings are substantially free of coating and amethod for manufacturing the medical device. In the method, afterapplying a coating composition to the surface of the medical device toform a coating thereon, coating present in the openings of the surfaceis ablated using an ultraviolet (UV) laser having pulse length shorterthan about 100 nanoseconds and a repetition rate less than about 100Hertz.

[0011] Another embodiment of the present invention is a method formanufacturing an expandable stent having a surface adapted for exposureto body tissue of a patient. At least a portion of the surface of thestent is comprised of a plurality of struts, and the struts are coveredwith a coating substantially free of cracks. In the method, afterapplying a coating composition to at least one of the struts to form acoating thereon, a portion of the coating on the strut is removed usingan ultraviolet (UV) laser, having pulse length shorter than about 100nanoseconds and a repetition rate less than about 100 Hertz, to preventthe coating from cracking.

DESCRIPTION OF THE FIGURES

[0012]FIG. 1 shows a schematic diagram of an embodiment of the presentinvention in which a scale, an ultraviolet (UV) laser and a computer isused to make a coated medical device having a particular desired amountof coating.

[0013]FIG. 2 shows a schematic view of a stent having a single-layeredcoating on its middle section and having a two-layered coating at an endof the stent.

[0014]FIG. 3 shows a schematic view of a stent having a partially coatedsurface, that is prepared by an embodiment of the invention.

[0015]FIG. 4 is a micrograph (at magnification×500) of a coated stentwherein a portion of the coating has been ablated.

[0016]FIG. 5 is a cross-sectional view of a coated medical devicewherein a portion of the coating is ablated to expose a portion of thesurface of the device.

DETAILED DESCRIPTION OF THE INVENTION

[0017] The present invention is directed to a method for manufacturingan implantable medical device having a surface covered with a coating,using an ultraviolet (UV) laser.

[0018] 1. Suitable Medical Devices

[0019] The method of the present invention is a method for manufacturingan implantable medical device having a surface adapted for exposure tobody tissue of a patient. The medical devices suitable for the presentinvention include medical devices having at least a portion of a curvedsurface, which include, but are not limited to, stents, catheters, suchas central venous catheters and arterial catheters, guidewires,cannulas, cardiac pacemaker leads or lead tips, cardiac defibrillatorleads or lead tips, implantable vascular access ports, blood storagebags, blood tubing, vascular or other grafts, intra-aortic balloonpumps, heart valves, cardiovascular sutures, total artificial hearts andventricular assist pumps, and extra-corporeal devices such as bloodoxygenators, blood filters, hemodialysis units, hemoperfusion units orplasmapheresis units.

[0020] Medical devices which are particularly suitable for the presentinvention include stents, for example, vascular stents such asself-expanding stents and balloon expandable stents. Stents suitable forthe present invention include any stent for medical purposes, which areknown to the skilled artisan. Examples of self-expanding stents usefulin the present invention are illustrated in U.S. Pat. Nos. 4,655,771 and4,954,126 issued to Wallsten and 5,061,275 issued to Wallsten et al.Examples of appropriate balloon-expandable stents are shown in U.S. Pat.No. 5,449,373 issued to Pinchasik et al. Similarly, urinary implantssuch as drainage catheters are also appropriate for the invention.Stents having a complicated geometry pattern are particularly suitablefor the method of the present invention. Examples of suitable stentsinclude a stent having a surface which has a plurality of openingstherein and a stent having a surface comprising a plurality of struts.

[0021] Appropriate materials for making the medical device of thepresent invention includes metals and polymers. Examples of suchpolymers include poly(ethylene terephthalate), polyacetal, poly(lacticacid), poly(ethylene oxide)/poly(butylene terephthalate) copolymer, andpolycarbonate. Examples of suitable metals include titanium, stainlesssteel, platinum, tantalum or gold/platinum alloy.

[0022] 2. Coating Compositions

[0023] In the present invention, any method for applying a coatingcomposition to a surface of a medical device to form a coating issuitable. Examples of suitable methods include dipping, spraying,covering, plating, co-extruding and immobilizing. More than one coatingmethod can be used to make a medical device. In the method of thepresent invention, any method for applying a coating composition knownin the art is suitably used regardless of whether the method givesbetter control over the amount of coating on a medical device andwhether the method provides less webbings in openings of a surface of amedical device. For example, a dip coating method can be used althoughthe method gives less control over the amount of coating applied to amedical device than a spray coating method and tends to cause webbing inthe openings of a surface of a medical device. A portion of the coatingapplied by dipping on a surface of a medical device can be ablated usingan ultraviolet (UV) laser in the method of the present invention asdescribed below in detail.

[0024] In the present invention, the term “applying in substantially thesame manner,” when referring to the application of a coatingcomposition, means applying the coating composition in a manner whereinsubstantially all the parameters which affect the thickness of thecoating formed are substantially identical. Such parameters includeambient temperature, humidity, air pressure, temperature of the coatingcomposition, concentration of the composition, and all physicalproperties of the coating composition, e.g., viscosity and adhesiveness.When the coating composition is applied by a spray coating method, thefactors further include spraying time and speed of the coatingcomposition at the nozzle of the spraying apparatus as well as the typeof nozzle employed, size of droplets and distance between the medicaldevice and the nozzle. When a dipping method is used, the factorsfurther include dipping time and speed of withdrawal of the medicaldevice from the coating composition. Preferably, when two or moremedical devices are coated in substantially same manner, they may becoated simultaneously. When two or more medical devices that are made ofthe same material and have substantially the same configuration and samedimensions, are coated in a substantially same manner, the thickness ofthe coating on each device can be presumed to be identical, and thethickness of the coating of one device is estimated by measuringthickness of the coating on the other device as explained in detail insection 5, infra.

[0025] Furthermore, before applying the coating composition, the surfaceof the medical device is optionally subjected to a pre-treatment, suchas roughing, oxidizing or priming. Exposing the surface of the device toa primer is a preferable as method of pretreatment.

[0026] The thickness of the coatings formed by the method of theinvention can range from almost a single layer of molecules to about 0.1mm. Suitable thicknesses for the coating are known in the art and can beselected by the skilled artisans.

[0027] Coating compositions suitable for the present invention include acoating material dispersed or dissolved in a solvent suitable for themedical device which is known to the skilled artisan. Suitable coatingmaterials include polymeric material, such as poly-L-lactic acid,polycarbonate, polyethylene terephtalate, silicones, polyurethanes,thermoplastic elastomers, ethylene vinyl acetate copolymers, polyolefinelastomers, hydrogels, ethylene-propylene-diene (EPDM) rubbers andstyrene-isobutylene-styrene (SIBS).

[0028] Also, the coating can be a drug-releasing coating whichimmediately or gradually releases a biologically active material.Coating polymers useful for drug coatings includes hydrogel polymerswhich are often used to contain the biologically active material and aredisclosed in U.S. Pat. No. 5,304,121, U.S. Pat. No. 5,464,650, PCTpublication WO95/03083 and U.S. Pat. No. 5,120,322, which areincorporated herein by reference. However, a non-hydrogel can be alsoused. Such coatings include biologically active molecules, such asheparine or insuline molecules, directly attached to oxide molecules onthe surface of the structure as explained below. Although polymericmolecules can be combined with biologically active molecules,biologically active materials can be directly immobilized on thepolymeric molecules on the surface of the medical device. As disclosedin U.S. Pat. No. 5,356,433 to Rowland et al., polysaccharides can beimmobilized to metallic surfaces by applying an organosilane coatingwith amine functionality and then applying a polysaccharide usingcarbodiimide as a coupling agent. U.S. Pat. No. 5,336,518 to Narayananet al. also discloses that a polysaccharide can be immobilized on asurface by applying a coat of heptafluorobutylmethacrylate (HFBMA) byradio-repetition rate (RF) plasma deposition, creating functional groupson the surface by RF plasma with water vapor, and then applying thepolysaccharide using carbodiimide. Moreover, examples of medicaldevices, in particular, stents coated with polymer/biologically activematerial coatings are described in U.S. Pat. No. 5,879,697 which isincorporated herein by reference.

[0029] The term “biologically active material” encompasses therapeuticagents, such as drugs, and also genetic materials and biologicalmaterials. The genetic materials mean DNA or RNA, including, withoutlimitation, of DNA/RNA encoding a useful protein stated below, intendedto be inserted into a human body including viral vectors and non-viralvectors. Viral vectors include adenoviruses, gutted adenoviruses,adeno-associated virus, retroviruses, alpha virus (Semliki Forest,Sindbis, etc.), lentiviruses, herpes simplex virus, ex vivo modifiedcells (e.g., stem cells, fibroblasts, myoblasts, satellite cells,pericytes, cardiomyocytes, sketetal myocytes, macrophage), replicationcompetent viruses (e.g., ONYX-015), and hybrid vectors. Non-viralvectors include artificial chromosomes and mini-chromosomes, plasmid DNAvectors (e.g., pCOR), cationic polymers (e.g., polyethyleneimine,polyethyleneimine (PEI)) graft copolymers (e.g., polyether-PEI andpolyethylene oxide-PEI), neutral polymers PVP, SP1017 (SUPRATEK), lipidsor lipoplexes, nanoparticles and microparticles with and withouttargeting sequences such as the protein transduction domain (PTD). Thebiological materials include cells, yeasts, bacteria, proteins,peptides, cytokines and hormones. Examples for peptides and proteinsinclude growth factors (FGF, FGF-1, FGF-2, VEGF, Endotherial MitogenicGrowth Factors, and epidermal growth factors, transforming growth factorα and β, platelet derived endothelial growth factor, platelet derivedgrowth factor, tumor necrosis factor α, hepatocyte growth factor andinsulin like growth factor), transcription factors, proteinkinases, CDinhibitors, thymidine kinase, and bone morphogenic proteins (BMP's),such as BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 (Vgr-1), BMP-7 (OP-1), BMP-8.BMP-9, BMP-10, BMP11, BMP-12, BMP-13, BMP-14, BMP-15, and BMP-16.Currently preferred BMP's are BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, BMP-7.These dimeric proteins can be provided as homodimers, heterodimers, orcombinations thereof, alone or together with other molecules. Cells canbe of human origin (autologous or allogeneic) or from an animal source(xenogeneic), genetically engineered, if desired, to deliver proteins ofinterest at the transplant site. The delivery media can be formulated asneeded to maintain cell function and viability. Cells include whole bonemarrow, bone marrow derived mono-nuclear cells, progenitor cells (e.g.,endothelial progentitor cells) stem cells (e.g., mesenchymal,hematopoietic, neuronal), pluripotent stem cells, fibroblasts,macrophage, and satellite cells.

[0030] Biologically active material also includes non-genetictherapeutic agents, such as:

[0031] anti-thrombogenic agents such as heparin, heparin derivatives,urokinase, and P-Pack (dextrophenylalanine proline argininechloromethylketone);

[0032] anti-proliferative agents such as enoxaprin, angiopeptin, ormonoclonal antibodies capable of blocking smooth muscle cellproliferation, hirudin, and acetylsalicylic acid, amlodipine anddoxazosin;

[0033] anti-inflammatory agents such as glucocorticoids, betamethasone,dexamethasone, prednisolone, corticosterone, budesonide, estrogen,sulfasalazine, and mesalamine;

[0034] antineoplastic/antiproliferative/anti-miotic agents such aspaclitaxel, 5-fluorouracil, cisplatin, vinblastine, vincristine,epothilones, methotrexate, azathioprine, adriamycin and mutamycin;endostatin, angiostatin and thymidine kinase inhibitors, taxol and itsanalogs or derivatives;

[0035] anesthetic agents such as lidocaine, bupivacaine, andropivacaine;

[0036] anti-coagulants such as D-Phe-Pro-Arg chloromethyl keton, an RGDpeptide-containing compound, heparin, antithrombin compounds, plateletreceptor antagonists, anti-thrombin anticodies, anti-platelet receptorantibodies, aspirin (aspirin is also classified as an analgesic,antipyretic and anti-inflammatory drug), dipyridamole, protamine,hirudin, prostaglandin inhibitors, platelet inhibitors and tickantiplatelet peptides;

[0037] vascular cell growth promotors such as growth factors, VascularEndothelial Growth Factors (FEGF, all types including VEGF-2), growthfactor receptors, transcriptional activators, and translationalpromotors;

[0038] vascular cell growth inhibitors such as antiproliferative agents,growth factor inhibitors, growth factor receptor antagonists,transcriptional repressors, translational repressors, replicationinhibitors, inhibitory antibodies, antibodies directed against growthfactors, bifunctional molecules consisting of a growth factor and acytotoxin, bifunctional molecules consisting of an antibody and acytotoxin;

[0039] cholesterol-lowering agents; vasodilating agents; and agentswhich interfere with endogenous vasoactive mechanisms;

[0040] anti-oxidants, such as probucol;

[0041] antibiotic agents, such as penicillin, cefoxitin, oxacillin,tobranycin

[0042] angiogenic substances, such as acidic and basic fibrobrast growthfactors, estrogen including estradiol (E2), estriol (E3) and 17-BetaEstradiol; and

[0043] drugs for heart failure, such as digoxin, beta-blockers,angiotensin-converting enzyme (ACE) inhibitors including captopril andenalopril.

[0044] A coating of a medical device of the present invention maycontain multiple coating layers. For example, the first layer and thesecond layer may contain different biologically active materials.Alternatively, the first layer and the second layer may contain anidentical biologically active material having different concentrations.Either of the first layer or the second layer may be free ofbiologically active material.

[0045] 3. Suitable Ultraviolet Lasers

[0046] In embodiments of the present invention, after a surface of amedical device is coated, a portion of the coating may be ablated usingan ultraviolet (UV) laser (light amplification by stimulated emission ofradiation). In the present invention, an “UV” or “ultraviolet” lasermeans a laser having wavelength less than about 400 nm. Preferably, thewavelength of the ultraviolet (UV) laser used in the method of thepresent invention is shorter than about 200 nm. Because of therelatively shorter wave length, the ultraviolet (UV) laser ablates acoating material by a photochemical reaction rather than a thermalreaction. Because the ablation is accompanied by substantially no heattransfer or a thermal shock, it does not cause serious damages, such ascracking to the coating material. Also, the ablated surface issubstantially free from redeposited or re-solidified material. For thesame reason stated above, such ultraviolet (UV) laser should have apulse length shorter than about 100 nano (10⁻⁹) seconds and a repetitionrate less than about 100 Hertz (Hz). Preferable examples of theultraviolet (UV) laser useful for the present invention include aneodymium YAG (Nd:YAG) (355 nm) laser, a triple harmonic frequency (THF)laser, an argon fluoride (ArF) laser having 193 nm wavelength and afluorine (F₂) laser having 152 nm wavelength. In particular, excimerlasers which are commercially available from Lamda Physik, Inc., can beused for a method of the present invention.

[0047] In one preferable embodiment of the present invention,ultraviolet (UV) laser ablation may be conducted with anultrashort-pulse laser. “Ultrashort-pulse lasers” refer to lasersconsisting of pulses with durations shorter than about 10 pico (=10⁻¹¹)second. The ultrashort-pulse lasers are known to artisans. For example,they are thoroughly disclosed by M. D. Perry et al. in Ultrashort-PulseLaser Machining, Section K-ICALEO 1998, pp. 1-20, which is incorporatedherein by reference. In the method of the present invention, because ofuse a laser having rather short pulse length, the laser ablation is veryaccurately controlled and creates substantially no heat.

[0048] The intensity (fluence) of the laser radiation that is requiredto trim a material is dependent on the material to be ablated. Byadjusting the intensity of the ultraviolet (UV) laser, it is possible toablate the entire thickness of the coating material and not to ablatethe substrate or the medical device. Alternatively, the thickness of thecoating is estimated before ablation, the intensity and/or pulse numberof the ultraviolet (UV) laser can be adjusted to properly ablate theestimated thickness. Specifically each material has its ownlaser-induced optical breakdown (LIOB) threshold which characterizes thefluence required to ablate the material at a particular pulse width.Also the fluence of the laser suitable for the present invention can bechosen according to the thickness of the coating. Furthermore, thenumber of pulses needed to ablate completely through a material can becalculated for a given energy or fluence. It is possible to choose anultraviolet (UV) laser having an appropriate intensity so that theultraviolet (UV) laser can trim the coating but cannot ablate the stentbody. For example, an ultraviolet (UV) laser can be adjusted to trim acoating material but does not ablate a metallic stent body. One ofordinary skill can choose the suitable intensity for ablating thecoating material.

[0049] In certain embodiments of the present invention, the coating onthe medical device has more than one layer. Using an ultraviolet (UV)laser adjusted to ablate only the top layer, it is possible to ablate aportion of the top layer substantially without damaging the otherlayer(s). Such ultraviolet (UV) laser can be adjusted based on thethickness of the top layer that is estimated as explained in section 5,infra. For example, it is possible to remove a portion of the top layerfrom a middle section of the coated medical device, such as a stent, andleave the top layer at the both end sections of the coated device. Forexample, if the top layer contains the same kind of the biologicallyactive material than that of the layer below at a higher concentration,then a medical device having a higher concentration of the biologicallyactive material at its two end sections than its middle section can beobtained. Alternatively, the portion of the top layer that is removedfrom a portion of the top layer can have various shapes, such as aspiral shape, a strip-like shape, or a ring shape.

[0050] Furthermore, the portion of the top layer can contain abiologically active material that is different from the one contained inthe under layer. Accordingly, a medical device which can release twodifferent biologically active materials is obtained. Alternatively, thetop layer can be substantially free of a biologically active materialand the under or inner layer can contain a biologically active material.By ablating a portion of a top layer, a coated medical device whereinthe coating containing a biologically active material covered with adiscontinuous top layer free of biologically active material can beachieved.

[0051] 4. Manufacturing a Coated Medical Device Having a Desired Amountof Biologically Active Material

[0052] In one embodiment of a method of the present invention, a coatedmedical device in which the coating contains a desired amount of abiologically active material is prepared. In this embodiment, the amountof biologically active material in a coating placed on a medical deviceis determined by a method known by one or ordinary skill in the art. Forexample, a medical device, such as a stent or portion thereof, which isto be coated is weighed. Then, a coating composition containing abiologically active material is applied to a surface of the device in amanner such that a coating containing an amount of biologically activematerial in excess of the desired amount of biologically active materialis formed. The coated device is weighed to determine the excess amountof biologically active material in the coating. Specifically, byweighing the coated device, the amount of coating placed on the devicecan be determined. Based on this amount of coating and concentration ofthe biologically active material in the coating composition, the skilledartisan can determine the amount of coating that contains the excessamount of the biologically active material. Afterwards, a portion of thecoating is ablated with an ultraviolet (UV) laser to obtain a coatedmedical device wherein the coating contains a desired amount ofbiologically active material. The desired amount of biologically activematerial may be a range having a minimum desired amount and a maximumdesired amount.

[0053] In the present invention, the term “weighing” encompasses allways of weighing. For example, a medical device can be hung or be placedon a plate for weighing. In one preferred embodiment, the device forweighing is connected to a fixture to which the medical device isattached during the laser ablation. The fixture is connected to a scaleso that the medical device can be continuously weighed. Preferably, theweighing device is connected to a computer which can record, compare andcalculate the weight data received from the weighing device.

[0054] In a preferred embodiment, the ultraviolet (UV) laser ablation iscontrolled by a computer which receives the weight data from theweighing device. FIG. 1 is a schematic diagram which shows how a scale,a laser and a computer relate to each other for conducting thisembodiment of the invention. A stent 10 is weighed by a scale 11. Theweight measured by the scale 11 is recorded by a computer 13. The flowof the data is shown by an arrow 12. After a coating composition isapplied to the surface of the stent, the stent 10 is weighed again byusing the scale 11. Based on the weight data received from the scale 11,the computer 12 determines the excess amount of the coating and commandsan ultraviolet (UV) laser 15 to ablate a portion of the coating toremove the excess. The flow of the command is shown by an arrow 14. Thedesired portion of the coating on the stent 10 is ablated by theultraviolet (UV) laser 15, and such action is shown by an arrow 16.

[0055] In one embodiment, the coated device may be weighed again afterablation to determine if there is still an excess amount of biologicallyactive material or coating on the device. In this embodiment, theseablation and weighing steps are repeated until a coated device havingthe desired amount of biologically active material in the coating isobtained.

[0056] In another embodiment, the thickness of the coating may beestimated before the ablation. In yet another embodiment, the size ofthe portion of the coating that is ablated is determined before theportion is ablated. Such size may be determined based on the weight ofthe coating to be ablated and an estimated thickness of the coating. Thethickness of the coating is estimated by a method explained in section5, infra.

[0057] Furthermore, a coating of a medical device of the presentinvention may consist of a plurality of coating layers. In oneembodiment of the present invention, a medical device covered by thecoating having the outermost layer containing a desired amount ofbiologically active material can be prepared. In this embodiment, onlythe outermost coating layer is ablated without ablating the underlayer(s). The thickness of the outermost layer may be estimated beforethe ablation, and the ultraviolet (UV) laser may be adjusted to ablatethe outermost layer but not the other layer(s).

[0058] 5. Estimation of Thickness of Coating

[0059] In one embodiment of the present invention, the thickness of acoating on a medical device can be measured. In such embodiment, aportion of a coating on a medical device is ablated with an ultraviolet(UV) laser to expose a portion of the surface of the medical device andcreate a step in the coating. By adjusting the intensity of theultraviolet (UV) laser, it is possible to ablate the entire thickness ofthe coating material and not to ablate the medical device.Alternatively, especially when the medical device is made of a polymer,the coated medical device is slowly ablated, and the chemicalcomposition of the ablated material is continuously detected using aninstrument, such as a mass spectrometer during the ablation. The laserablation is continued until the chemical composition of the materialthat makes up the medical device is detected, indicating that the entirethickness of the coating has been ablated through.

[0060] The term “step” in the present invention means a structuresimilar to a step of a stairway as shown in FIG. 5. In FIG. 5, a portionof a coating 52 is ablated to expose a portion of surface of the medicaldevice 50. A step comprises a portion of the medical device's surface54, the cross-section 56 of the coating 52 and a portion of thecoating's surface 58. The thickness a of the coating can be determinedby measuring the height of the step.

[0061] The step height, i.e., a thickness of the coating, can beoptically measured by using a white light interferometer. White light isdefined as polychromatic light which contains lights of variouswavelength. An interferometer is an optical instrument for measuring thethickness of a layer. The “Michelson interferometer” is a well-knownexample of an interferometer. A white light interferometer iscommercially available, for example from Zygo Corporation. In apreferred embodiment of the present invention, the white lightinterferometer is connected to a computer wherein the data obtained bythe white light interferometer is processed. Preferably, the computeralso receives the weight data and controls the ultraviolet (UV) laserablation of the coating. NEWVIEW™ 5000 sold from Zygo Co. and WYKONT3300™ from VEECO Instruments are examples for such systems that arecommercially available.

[0062] In embodiments of the present invention, a thickness of a coatingof a coated medical device is estimated before the coating is ablated.Specifically, a second medical device, which is made of the samematerial as a first medical device that is to be coated and havingsubstantially the same configuration and dimensions as the firstmedical, is weighed. Then, a coating composition is applied to a surfaceof the second device in a substantially same manner as the coatingcomposition that was applied to a surface of the first medical device.The measured thickness of the coating on the second medical device isused as an estimated thickness of the coating on the first medicaldevice. In one embodiment, two or more portions of the coating on thesecond medical device are ablated using an ultraviolet (UV), and thethicknesses at each portion of coating are determined. An average istaken of these thicknesses. The average thickness of the coating on thesecond medical device is used as an estimated thickness of the coatingon the first medical device. In yet another embodiment, at least oneadditional medical device is used in conjunction with the second medicaldevice to estimate the coating thickness. After determining thethickness of the coating on each medical device, an average of thethicknesses is used as the estimated thickness of the coating on thefirst medical device.

[0063] Moreover in another embodiment of the present invention, acoating comprises a plurality of layers. The thickness of the secondlayer is estimated by measuring the thickness of coating layer(s) beforeand after the second layer is applied. Specifically, to estimate thethickness of the second layer of a first coated medical device whereinthe coating has the second layer and a first layer, a second medicaldevice and a third medical device are used. After applying a firstcoating composition to the surfaces of each medical device to be coatedin substantially same manner to form a first layer of the coating, thethickness of the first layer of the second medical device is measured asexplained above. Afterward, a second coating composition is applied tothe first and third medical devices in substantially the same manner toform the second layer of the coating. The total thickness of the secondlayer and the first layer of the third medical device is measured asexplained above, i.e., by creating a step in the entire coating andmeasuring thickness thereof. By subtracting the thickness obtained forthe first layer of the second medical device from the total thickness ofthe coating obtained for the third medical device. The thickness of thesecond layer in the coating on the third medical device is obtained. Thethickness of the second layer of the first medical device is estimatedas the thickness of the second layer of the third medical device. In asimilar manner, the thickness of a layer in a coating having three ormore layers can also be estimated by using more medical devices.

[0064] In another embodiment, more than one portion of the coating onthe second medical device and/or the third medical device are ablatedusing an ultraviolet (UV), and the thickness of the coating at eachportion is determined and averaged. The average of the measuredthicknesses is used to estimate the thickness of the second layer of thefirst medical device. In yet another embodiment, at least one additionalmedical device is used in conjunction with the second and/or thirdmedical device. For instance, the additional medical device can becoated only with the first layer like the third medical device. Afterdetermining the thicknesses of the first layer on the third and theadditional medical device(s), an average of the thicknesses is used toestimate the thickness of the second layer on the first medical device.

[0065] 6. Coated Medical Devices with a Portion of Their CoatingsRemoved

[0066] In other embodiments of the invention, a portion of coating on acoated medical device is ablated by an ultraviolet (UV) laser. In oneembodiment, after estimating the thickness of a top layer of the coatingof a medical device coated with an under layer and a top layer (seesection 5, supra), the top layer is ablated only at the middle portionof the coated device. An ultraviolet (UV) laser adjusted based on theestimated thickness of the top layer is used to ablate or remove thisportion of the top layer. In another embodiment, the top layer is slowlyablated or removed without estimation of thickness using ultraviolet(UV) laser while the chemical composition of the ablated material iscontinuously detected using an instrument, such as a mass spectrometer.The laser ablation is continued until the chemical composition of theunder layer is detected. The coated device obtained after theabove-mentioned laser ablation has at least two layers of coating atboth ends of the device but one fewer layer at the middle of the device.An example of such a device is shown in FIG. 2. A stent 20 comprisingstruts 23 is coated with an under layer 24 containing a biologicallyactive material on entire surface of the stent 20. Because the top layerof the coating near the middle of the stent has been ablated, there isno top layer of coating at the middle of the stent. However, at the endsof the stent, there is a top coating layer 25 of coating containing ahigher concentration of the biologically active material. Each portionof the ends and of the middle portion of the stent is shown in amagnified cross-sectional view 21 and 22, respectively.

[0067] Furthermore, depend on its geometry, a medical device, such as astent may have a portion where a thick coating placed on its surface mayeasily crack and cause problems. For example, when an expandable stenthas a plurality of struts which are in close proximity to each other,the coating on the struts may adhere to each other when the stent iscollapsed to be loaded into a delivery sheath. When the stent isdeployed, the adhered coating may be torn off the stent. Also, in anexpandable stent, there are portions in struts which are subjected tosignificant expansion forces, e.g., the portions 32 in FIG. 3. A coatingon such portions has a great risk of cracking when the stent expands. Inone embodiment of the present invention, portions of coating on anindividual strut can be ablated with the ultraviolet (UV) laser toreduce such cracking or tearing. In FIG. 3, an expandable stent 30 isschematically shown. A portion of the stent 30 is magnified in circle 31wherein shaded portions 32 indicate those portions of the coating in thestrut that tend to crack or tear. The coating on the portion 32 isablated with an ultraviolet (UV) laser ablation to prevent the crackingor tearing. In another embodiment, the coating at such portions 32 isnot entirely ablated but may be thinned or made thinner leaving somecoating to cover the device at those portions. Such ablation may beconducted using a ultraviolet laser which is adjusted to ablate only thecoating material but not the medical device material or using aultraviolet laser which is adjusted to ablate the thickness of thecoating estimated beforehand.

[0068] 7. Removing Webbing

[0069] When a medical device, such as a stent, has a sidewall made ofstruts that form openings therein, application of a coating compositionmay form not only a coating on the surface of the struts but alsoundesired webbing in the openings. A “webbing” is an excess coatingmaterial which bridges at small gaps or corners between stent struts andentirely or partially blocks the openings. Webbing is undesirablebecause it can separate from the device while it is implanted in apatient. Such separated or loose webbing can cause emboli. Dip coatingtends to create an undesired amount of webbing of coating material. Suchwebbing can be ablated with the ultraviolet (UV) laser described above.Preferably, the ultraviolet (UV) laser is adjusted to ablate only thecoating but not the medical device.

[0070] In a preferred embodiment, the ultraviolet (UV) laser ablation toremove the webbing is computer-controlled. Also, when the medical deviceused for the method of the present invention has an expandable portion,such ultraviolet (UV) laser ablation may be conducted while the deviceis in its expanded state.

EXAMPLE

[0071] A stent made of stainless steel 316LVM was coated with a coatingcomposition [coating polymer: styrene isobutylene styrene (SIBS),solvent: tetrahydrofuran (THF)]. A portion of the coating was ablatedwith an ultraviolet (UV) laser without ablating the stent body. Theultraviolet laser has the following properties: wavelength 193 nm,repetition rate 50 Hertz, number of pulses from 95 to 100, pulseduration 10 nano seconds and laser fluence 0.15/cm². A micrograph atmagnification×500 of the portion of the stent is shown as FIG. 4. Therectangular portion in white shown in the middle of FIG. 4 is an exposedmetal surface from which the coating is removed by the ultraviolet (UV)laser ablation. The step height system of the coating was measured witha white light interferometer by using a NEWVIEW™ (Zygo Co.) system. Thestep height, i.e., the coating thickness was determined to be 19 μm.

[0072] The description contained herein is for purposes of illustrationand not for purposes of limitation. Changes and modifications may bemade to the embodiments of the description and still be within the scopeof the invention. Furthermore, obvious changes, modifications orvariations will occur to those skilled in the art. Also, all referencescited above are incorporated herein, in their entirety, for all purposesrelated to this disclosure.

What is claimed is:
 1. A method for manufacturing an implantable medicaldevice having a surface adapted for exposure to body tissue of apatient, wherein at least a portion of the surface is covered with acoating having a desired amount of a biologically active material, saidmethod comprising: (a) providing a first medical device having asurface; (b) applying to a portion of the surface of the first medicaldevice a coating composition comprising the biologically active materialin a manner such that a coating containing an amount of the biologicallyactive material in excess of the desired amount of biologically activematerial is formed on the surface of the first medical device; (c)determining the amount of biologically active material in the coatingthat is in excess of the desired amount of biologically active material;and (d) ablating a portion of the coating containing the amount ofbiologically active material in excess of the desired amount using anultraviolet (UV) laser.
 2. The method of claim 1, wherein theultraviolet laser has pulse length shorter than about 100 nanosecondsand a repetition rate less than about 100 Hertz.
 3. The method of claim1, wherein the step (c) is conducted by weighing the first medicaldevice before and after application of the coating composition on thesurface of the first medical device.
 4. The method of claim 1 whereinthe surface of the first medical device is curved.
 5. The method ofclaim 1 wherein only the coating but not the first medical device isablated.
 6. The method of claim 1 wherein the coating comprises morethan one layer, and the ablating step (d) is conducted on only theoutermost layer of the coating.
 7. The method of claim 1, wherein thesteps (c) and (d) are repeated as necessary until the coating containsthe desired amount of biologically active material.
 8. The method ofclaim 1 wherein, before the coating is ablated, the thickness of thecoating is estimated by: (i) applying to at least a portion of a surfaceof a second implantable medical device the coating composition, insubstantially the same amount and same manner that was used to form thecoating on the surface of the first medical device, to form a coating onthe surface of the second medical device, wherein the first and secondmedical devices are made of the same material and have substantially thesame configurations and dimensions; (ii) ablating a portion of thecoating of the second medical device with the ultraviolet (UV) laser toexpose a portion of the surface of the second medical device and tocreate a step having a height in the coating; (iii) determining thethickness of the coating of the second medical device by measuring theheight of the step using a white light interferometer; and (iv)estimating the measured thickness of the coating of the first medicaldevice based on the thickness of the coating of the second medicaldevice.
 9. The method of claim 8 which further comprises repeating steps(ii) and (iii) using a different portion of the coating of the secondmedical device and wherein an average of the measured thicknesses of thecoating of the second medical device is obtained and wherein thethickness of the coating of the first medical device is estimated basedupon the average.
 10. The method of claim 8 which further comprisesconducting steps (i), (ii) and (iii) using at least one additionalimplantable medical device; and wherein an average of the measuredthickness of the coating of the second medical device and the measuredthicknesses of the coating of the additional medical device(s) isobtained; and wherein the thickness of the coating of the first medicaldevice is estimated based upon the average.
 11. The method of claim 1wherein the laser has a wavelength between about 157 nm and about 193nm.
 12. The method of claim 1 wherein the coating composition comprisesa polymeric material which is selected from the group consisting ofpoly-L-lactic acid, polycarbonate, polyethylene terephtalate, silicones,polyurethanes, thermoplastic elastomers, ethylene vinyl acetatecopolymers, polyolefin elastomers, hydrogels and ethylene-propylenediene(EPDM) rubbers.
 13. A method for manufacturing an implantable medicaldevice having a surface adapted for exposure to body tissue of apatient, wherein at least a portion of the surface is covered with acoating having at least two layers, and wherein the coating comprises abiologically active material, said method comprising: (a) applying to atleast a portion of a surface of a first implantable medical device afirst coating composition to form a first layer of the coating; (b)applying to the first layer of the first medical device a second coatingcomposition to form a second layer of the coating thereon; and (c)ablating a portion of the second coating layer using an ultraviolet (UV)laser.
 14. The method of claim 13, wherein the ultraviolet laser has apulse length shorter than about 100 nanoseconds and a repetition rateless than about 100 Hertz.
 15. The method of claim 13 wherein thesurface of the first medical device is curved.
 16. The method of claim13 wherein the portion of the second layer is ablated in a manner suchthat the first layer is substantially not ablated.
 17. The method ofclaim 13 wherein at least one of the first layer and the second layercomprises a biologically active material.
 18. The method of claim 13wherein at least one of the first coating composition and the secondcoating composition is substantially free of a biologically activematerial.
 19. The method of claim 13, wherein the medical device is astent comprising a first end, a second end and a middle section andwherein the portion of the second layer that is ablated is located atthe middle section of the stent.
 20. The method of claim 19 wherein thefirst layer and the second layer both comprise a biologically activematerial and wherein the concentration of the biologically activematerial in the first layer is less than the concentration of thebiologically active material in the second layer.
 21. The method ofclaim 13 which further comprises estimating the thickness of the secondlayer of the first medical device.
 22. The method of claim 21 whereinthe thickness of the second layer of the first medical device, isestimated by: (i) applying to at least a portion of a surface of asecond implantable medical device and a surface of a third implantablemedical device the first coating composition, in substantially the samequantity and manner that was used in applying the first coatingcomposition to the surface of the first medical device, to form firstlayers on the surfaces of the second and third medical devices, whereinthe first, second and third medical devices are made of the samematerial and have substantially the same configurations and dimensions;(ii) ablating a portion of the first layer of the second medical devicewith an ultraviolet (UV) laser, having a pulse length shorter than about100 nanoseconds and a repetition rate less than about 100 Hertz, toexpose a portion of the surface of the second medical device and tocreate a first step having a height in the first layer; (iii)determining the thickness of the first layer of the second medicaldevice by measuring the height of the first step obtained in step (ii)using a white light interferometer; (iv) applying to the first layer ofthe third medical device the second coating composition, insubstantially the same quantity and manner that was used in applying thesecond coating composition to the first layer of the first medicaldevice, to form a second layer on the third medical device; (v) ablatinga portion of the first and second layers of the third medical devicewith an ultraviolet (UV) laser, having a pulse length shorter than about100 nanoseconds and a repetition rate less than about 100 Hertz, toexpose a portion of the surface of the third medical device and tocreate a second step having a height in the first and second layers;(vi) determining the total thickness of the first and second layers ofthe third medical device by measuring the height of the second stepobtained in step (v) by using a white light interferometer; and (vii)estimating the thickness of the second layer of the first medical devicebased upon the difference between the total thickness obtained in step(vi) and the thickness of the first layer obtained in step (iii). 23.The method of claim 22 which further comprises repeating steps (ii) and(iii) using a different portion of the first layer of the second medicaldevice and obtaining an average of the measured thicknesses of the firstlayer of the second medical device and wherein the average is used toestimate the thickness of the second coating layer of the first medicaldevice in step (vii).
 24. The method of claim 22 which further comprisesconducting steps (i), (ii) and (iii) using at least one additionalmedical device; and obtaining an average of the measured thickness ofthe first layer of the second medical device and the measured thicknessof the first layer of the additional medical device(s); and wherein theaverage is used to estimate the thickness of the second layer of thefirst medical device in step (vii).
 25. The method of claim 22 whichfurther comprises repeating steps (v) and (vi) using a different portionof the first and second layers of the third medical device and obtainingan average of the measured total thicknesses of the first and secondlayers of the third medical device and wherein the average is used toestimate the thickness of the second layer of the first medical devicein step (vii).
 26. The method of claim 22 which further comprisesconducting steps (iv), (v) and (vi) using at least one additionalmedical device; and obtaining an average of the measured total thicknessof the first and second layers of the second medical device and themeasured total thickness of the first and second layers of theadditional medical device(s) is obtained; and wherein the average isused to estimate the thickness of the second layer of the first medicaldevice in step (vii).
 27. The method of claim 13 wherein the firstcoating composition comprises a polymeric material selected from thegroup consisting of poly-L-lactic acid, polycarbonate, polyethyleneterephtalate, silicones, polyurethanes, thermoplastic elastomers,ethylene vinyl acetate copolymers, polyolefin elastomers, hydrogels andetylene-propylene-diene (EPDM) rubbers.
 28. The method of claim 13wherein at least either the first layer or the second layer comprises abiologically active material.
 29. A method for measuring a thickness ofa coating applied to at least a portion of a surface of an implantablemedical device comprising: (a) ablating a portion of the coating with anultraviolet (UV) laser having pulse length shorter than about 100nanoseconds and a repetition rate less than about 100 Hertz to expose aportion of the surface of the medical device and to create a step havinga height in the coating; and (b) determining the thickness of thecoating by measuring the height of the step by using a white lightinterferometer.
 30. The method of claim 29 which further comprisesrepeating steps (a) and (b) using a different portion of the coating andwherein an average of the measured thickness of the coating is obtained.31. A method for manufacturing a medical device having a surface adaptedfor exposure to body tissue of a patient, wherein the surface has aplurality of openings therein, and wherein at least a portion of thesurface is covered with a coating in a manner such that the openings aresubstantially free of coating, said method comprising: (a) applying acoating composition to the surface of the medical device to form acoating thereon; and (b) using an ultraviolet (UV) laser having pulselength shorter than about 100 nanoseconds and a repetition rate lessthan about 100 Hertz to ablate coating present in the openings of thesurface.
 32. The method of claim 31 wherein the coating compositioncomprises a biologically active material.
 33. A device manufacturedaccording to the method of claim
 31. 34. The method of claim 31 whereinthe ultraviolet (UV) laser has a wavelength between about 157 nm andabout 193 nm.
 35. A method for manufacturing an expandable stent havinga surface adapted for exposure to body tissue of a patient, and whereinat least a portion of the surface of the stent comprises a plurality ofstruts and wherein the struts are covered with a coating substantiallyfree of cracks, said method comprising: (a) applying a coatingcomposition to at least one of the struts to form a coating thereon; and(b) using an ultraviolet (UV) laser, having pulse length shorter thanabout 100 nanoseconds and a repetition rate less than about 100 Hertz,to remove a portion of the coating on the strut to prevent the coatingfrom cracking.
 36. The method of claim 35 wherein at least one of thestruts comprises at least one bend and wherein the portion of thecoating on the strut that is removed is located at the bend.